This proposal addresses the role of insulin resistance as a factor in the abnormal protein metabolism of chronic renal failure. Using a well characterized muscle perfusion system we will study uremic and sham- operated rats to determine dose response curves for insulin versus glucose and amino acid transport, as well as muscle protein synthesis and degradation rates. Uremic animals will be studied during perfusion with both physiologic and pharmacologic concentrations of insulin. Individual rates of skeletal muscle protein synthesis, total hemicorpus protein and myofibrillar protein degradation will be determined in both fed and fasted animals. The site of insulin resistance in uremia will be determined by examination of the known steps within the pathways of protein synthesis and degradation. The role of leucine, another regualor of protein turnover whose site of action cannot be distinguished from that of insulin, will also be examined. The cause of the insulin resistance, as well as the time course of its development, will be assessed in independent studies using, where appropriate, "uremic" perfusate and acutely versus chronically uremic animals. We have developed a chronically hyperinsulinemic uremic rat model to examine the possibility that weight gain and muscle protein anabolism can be improved in uremia with exogenous insulin supplementation. Studies will be performed both in vivo and in vitro comparing protein turnover in these animals with both uremic and sham-operated controls not receiving insulin supplementation. These studies have a direct bearing upon the abnormal protein metabolism, deminished weight gain and decreased muscle mass seen in patients, particularly children, with chronic renal insufficiency. A better understanding of these abnormalities could lead to improvements in the care of these individuals as well as a better understanding of the regulation of protein turnover under diverse physiologic conditions.